Mental disease, including schizophrenia, depression and autism spectrum disorders, are still poorly understood, although it is clear that they mostly represent cortical disorders. The cortex is the primary site of higher mental functions, and despite extensive research, there is still no unified theory of how the cortex works. This is partl due to the fact that neuroscientists have traditionally relied on microelectrodes to record the activity of individual cells. However, cortical circuits are composed of millions of neurons and it is conceivable that single cell measurements alone will not be sufficient to unravel function of the brain. Optical imaging techniques tackle this emergent level of neuronal circuit activity and enable to image the activity of neuronal ensembles, in vitro and in vivo, while preserving single cell resolution, something that brain imaging techniques such as MRI or PET, cannot do. Moreover, the development of genetically encoded photosensitive proteins (optogenetics) and optochemical (caged) compounds offers the opportunity to not only image the activity of many neurons but also to optically control them. In spite of their potential, current optical imaging techniques suffer form the fact that they rely on lasers which have to be moved to each pixel to build an image, making the imaging slow. Moreover, common laser microscopy is performed in 2D. To supersede those problems, we have recently developed a novel form of microscopy that uses spatial light modulators (SLM), to split the laser beam into a holographic pattern that can be used to image (or photoactivate) neurons simultaneously in 3D. SLM microscopy has the potential of becoming the ideal method with which to explore the role of neural circuits in brain diseases. Boulder Nonlinear Systems and Columbia University propose to combine their expertise in building SLMs and in SLM microscopy in a two-phase project with the ultimate goal of making SLM microscopy a practical reality in neuroscience and clinical research. In the first phase we plan to build a compact, inexpensive, user- friendly system that enables fast, 3D imaging and photoactivation of neurons. The device will be self-aligning and integrated with appropriate software so that it can be used, out of the box, for applications in several neurobiological projects including imaging intact neural network activity, optical manipulation of neuronal firing, functional mapping of brain connectivity, investigating neurovascular coupling, and also be used for assaying neuronal activity in animal models of brain disease. In Phase II we will extend the design to support electrophysiological recording with two-photon excitation, allowing 3D imaging and photostimulation of cortical neurons in living animals, such as awake behaving rodent preparations. PUBLIC HEALTH RELEVANCE: Microscopy with spatial light modulators (SLMs) enables use of optical techniques to study neuronal circuit activity, to both monitor and manipulate the activity of neuronal ensembles, in vitro and in vivo. Boulder Nonlinear Systems and Columbia University propose the development of a compact, inexpensive, user-friendly SLM based microscope (Pocketscope) that enables fast, 3D imaging and photoactivation of neurons. The device will find widespread use in neuroscience research including imaging intact neural network activity, optical manipulation of neuronal firing, functional mapping of brain connectivity investigating neurovascular coupling, and also be used for assaying neuronal activity in animal models of brain disease.